One common feature of neoplastic cells is evasion of TGF-b1-mediated growth inhibitory effects. We are interested in two B-cell lymphoma cell lines, DB and RL, that are resistant to TGF-b1-mediated growth suppression. We have reported previously that low dose PMA rendered RL cells sensitive to TGF-b1, whereas DB cells remained insensitive. Regarding the unresponsiveness of RL cells to TGF-b1-mediated growth suppression, we have found that the transient TGF-b1 signaling is responsible for the resistance. Analysis of TbRII revealed ligand-induced receptor down-regulation in a time-dependent manner. With a low dose of PMA, RL cells restored the sensitivity to TGF-b1 by stabilizing TbRII and sustaining TGF- signaling. The PMA effects were due to MEK activation and the stabilization of TbRII through binding to activated MEK1. The MEK inhibitor U0126 blocked PMA-induced up-regulation of TbRII. In HaCaT and BJAB cells, two TGF-b-sensitive cell lines, U0126 induced down-regulation of TbRII and blocked subsequent TGF-b signaling. In HEK293A cells, constitutively active MEK1, but not constitutively active ERK2, induced up-regulation of TbRII. Furthermore, TbRII physically interacted with the constitutively active MEK1, but not with wild type MEK1, indicating involvement of active MEK1 in stabilizing TbRII. Collectively, our data suggest a novel mechanism for MEK1 in regulating the sensitivity of cells to TGF-b signaling by stabilizing TbRII. We have also shown recently that TGF-1 suppresses growth of B-cell lymphoma cells by p14ARF-dependent regulation of mutant p53. In RL and CA46, two B cell lymphoma cell lines, TGF-1 treatment caused down-regulation of E2F-1 transcription factor resulting in the down regulation of both p14ARF and mutant p53, leading to growth arrest. Experimental overexpression of E2F-1 increased p14ARF level and blocked TGF-1-induced down regulation of p14ARF. Overexpression of p14ARF blocked the down-regulation of mutant p53, and prevented growth arrest. p14ARF also attenuated TGF-1-induced p21Cip1/WAF1 induction, which was reversible by p53 siRNA, indicating involvement of mutant p53 in controlling TGF-1-induced expression of p21Cip1/WAF1. The interaction observed between phospho-Smad2 and mutant p53 in the nucleus could be the mechanism responsible for blocking the growth suppressive effects of TGF- 1. In RL cells, p14ARF is present in a trimer consisting of mutant p53-Mdm2-p14ARF, and in a dimer consisting of Mdm2-p14ARF. Since it is known that Mdm2 can degrade p53, it is possible that, in its trimeric form, p14ARF is able to stabilize mutant p53 by inhibiting Mdm2. In its dimeric form, p14ARF may be sequestering Mdm2, limiting its ability to degrade p53. Collectively, these data demonstrate a unique mechanism in which the inhibition of TGF-1-mediated growth suppression by mutant p53 can be reversed by the down-regulation of its stabilizing protein p14ARF. This work suggests that the high levels of p14ARF often found in tumor cells could be a potential therapeutic target.